Orthopedic procedures involving the directed formation of new bone tissue benefit from implantation of biomaterials that stimulate and guide the repair process. The physical properties of the biomaterials in terms of composition and architecture influence the early integration of new bone tissue and ideally enable progressive replacement with natural bone without biological or structural incompatibilities at the implant site. Furthermore, the parallel delivery of therapeutic agents in conjunction with the biomaterials provide for improved clinical outcomes through the acceleration of the bone formation process, the improvement of bone quality, the concomitant reduction of pain, the prophylactic control of infection and other clinical benefits.
Orthopedic surgeons have historically used autograft (bone removed from the patient) as the biomaterial of choice to repair areas of the skeleton damaged by trauma or disease. Discussion on Dental Structure and Dental Caries, Proc R Soc Med. 1946 August; 39(10): 637-645. However, high incidences of donor site morbidity, the necessity of a painful second ‘harvesting’ surgical procedure, and the absence of large quantities of bone available for grafting compromises patient outcomes. Alternate natural sources of bone tissue have also been utilized in the form of allografts (bone taken from a cadaver) and xenografts (bone obtained from animals). However, these are not ideal options due to significant concerns related to: (1) transmission of disease, (2) difficulty of procurement and processing, (3) uncertain immune response, and (4) premature resorption.
In recognition of the limitations of natural bone tissue sources, significant innovation has occurred in the development of synthetic substitutes that attempt to mimic the beneficial features of natural bone while precluding the negative effects. Duplicating the performance advantages of natural bone tissue is challenging as the chemistry, biology and structure of the tissue are all influential in promoting successful orthopedic repair. Uchida, A. et al., The Use of Ceramics for Bone Replacement, The Journal of Bone and Joint Surgery, 66-B, 269-275 (1984).
The clinical performance of biomineral-based implants has shown that the chemistry of the implant-bone interface is improved through the use of materials that employ calcium phosphate or similar inorganic compositions. As the main inorganic component of bone consists of a highly substituted calcium phosphate apatite, researchers concerned with developing synthetic bone substitutes have concentrated on the various forms of calcium phosphate. These include hydroxyapatite, carbonated apatite, fluoroapatite, α and β tricalcium phosphate, tetracalcium phosphate, octacalcium phosphate, and combinations thereof. In general, these materials have proven to be both biocompatible and osteoconductive and are well tolerated by host tissues. Anna Rita Calafiori et al., Low Temperature Method for the Production of Calcium Phosphate Fillers, BioMedical Engineering OnLine, 3:8 (2004); and Franz-Xaver Huber et al., First Histological Observations on the Incorporation of a Novel Nanocrystalline Hydroxyapatite Paste OSTIM® in Human Cancellous Bone, BMC Musculoskeletal Disorders, 7:50 (2006).
The important role of biomineral chemistry is highlighted in U.S. Pat. No. 6,323,146 which discloses a synthetic biomaterial compound (Skelite™) composed of silicon-substituted calcium phosphate. Extensive testing demonstrated that this compound is ideally suited for use as a bone substitute material because it is: (1) 100% synthetic, (2) biocompatible, (3) able to participate in the body's natural bone remodeling process, and (4) relatively inexpensive to produce.
A number of other formulations of cements have been developed for orthopedic and/or dental applications. For example, U.S. Pat. No. 5,092,888 provides a hardening material comprising a powder component composed of a mixture of tetracalcium phosphate and calcium phosphate having a Ca/P atomic ratio lower than 1.67 and a liquid component composed of a colloidal aqueous solution comprising solid colloid particles dispersed in an aqueous medium. Also, U.S. Pat. No. 5,180,426 provides a calcium phosphate type setting material comprising a powder composed of at least one of α-tricalcium phosphate and tetracalcium phosphate and an aqueous acidic setting solution comprising at least one polysaccharide selected from the group consisting of carboxymethyl chitin, glycol chitin, pullalan, high methoxy-pectin and chitosan. U.S. Pat. No. 6,949,251 provides a composition comprising porous β-tricalcium phosphate granules that have a particle size of 0.1-2 mm and that comprise a multiplicity of pores having a pore diameter size of 20-500 μm and being single separate voids partitioned by walls and being not interconnected. U.S. Pat. No. 5,152,836 provides a calcium phosphate cement comprising tertiary phosphate and a calcium secondary phosphate with a molar ratio of Ca/P of 1.400 to 1.498.
The presence of porosity in an orthopedic implant has been recognized as being valuable by many researchers. This has led to a variety of bioceramic implants that can offer porosity of a size that enables new tissue ingrowth, see for example, U.S. Pat. Nos. 3,899,556; 3,929,971; 4,654,314; 4,629,464; 4,737,411; 4,371,484; 5,282,861; 5,766,618; and 5,863,984.
A common technique for producing porous ceramic bodies involves the use of pore forming agents that are removed prior to implantation of the ceramic body; see for example, U.S. Pat. Nos. 4,629,464; 4,654,314; 3,899,556; and International Patent Publication WO 95/32008.
U.S. Pat. No. 4,629,464 discloses a method in which thermally decomposable powdery material (crystalline cellulose) was mixed with hydroxyapatite (HA) powder and dry-pressed into a desired form. Subsequent thermal processing was used to sinter the HA particles together, providing increased strength, and to create pores in the HA matrix through decomposition of the crystalline cellulose material.
A variation of this technique is disclosed in U.S. Pat. No. 4,654,314 in which bubbled albumen was combined with a calcium phosphate powder and cast into a mold of a desired shape. Subsequent thermal processing hardened, carbonized, and volatilized the albumen pore forming agent, producing a sintered porous calcium phosphate ceramic.
U.S. Pat. No. 3,299,971 discloses a method of producing a porous synthetic material for use in hard tissue replacement. In this method, a porous carbonate skeletal material of marine life (coral) is converted into a porous hydroxyapatite material through a hydrothermal chemical exchange with a phosphate. The final microstructure of the converted hydroxyapatite material is essentially the same as that of the coral from which it was formed. Consequently, pore size is dependent on the type of coral used. While these porous structures possess the appropriate pore size and pore connectivity for hard tissue in-growth, the structure is limited to that of the selected coral and so the production of implants with a solid shell surrounding the porous network (typical of cortical or long bone, for example) is unobtainable. In addition, the bone grafts manufactured using this technique are characterized by poor mechanical properties and are difficult to handle and shape and cannot be secured using standard fixation techniques.
U.S. Patent Publication 2006/0198939 discloses a method of coating a porous calcium phosphate matrix with a polymer to increase the mechanical stability of the matrix and prevent the calcium phosphate matrix from cracking and the pieces from separating.
U.S. Pat. No. 6,485,754 discloses hydroxyapatite based bone cements that contain a cationic antibiotic.
While techniques to form porosity in a bioceramic implant have been established, these techniques are not applicable to a calcium-based cement that has to maintain its moldable property to enable the material to deform and match the contour of the surgical site. Foaming cements have been reported whereby a cement is mixed with a foaming agent that develops bubbles that ultimately generate porosity at the implant site (see US Patent Pub. 2007/0283849). The challenge with this approach is that the implant foaming agent is frequently exhausted prior to implantation, leading to a final product lacking the desired pore size and/or density.
Beyond the formation of a cement-based implant with appropriate chemistry, geometry, structural strength and bone integration, there is the desire to utilize orthopedic implants for the concurrent delivery of therapeutic agents that aid in the repair process.
It is apparent from the aforementioned prior art that a variety of methods have been developed to manufacture bone cements that utilize a biomineral composition. However, current methods and implants possess several shortcomings that make the resultant function of the implant less than satisfactory in terms of new tissue formation, implant stability and long term implant replacement with natural bone. Furthermore, these implants do not provide the capability to effectively deliver therapeutic agents that improve the clinical conditions for the patient.